White blood cells called T lymphocytes play critical roles in immune defense against viruses, bacteria, fungi, protozoa, and cancer cells. They are also involved in allergies / and in autoimmune diseases. T cells develop in a gland called the thymus, where they learn to distinguish the natural components of the body from the mutant proteins in tumor cells or those produced by infectious agents. This involves allowing cells with useful surface receptors to mature and eliminating cells with inappropriate receptors before they can become dangerous. This selection must work properly to generate T cells needed for effective responses to invading organisms and cancer, without allowing development of those cells harmful to normal body tissues. One goal of our work is to understand how this "education / selection" process occurs. Because T receptors see foreign substances (antigens) in the form of peptide-major histocompatibility complex (MHC) molecule complexes, we also wish to know how such materials guide development in the thymus and the activities of mature T cells in the body. We have been able to separate thymocyte lineage commitment to the CD4 or CD8 pathways from subsequent differentiation in each of these pathways, to determine the role of ligand quality and coreceptor signaling in making the commitment decision. The recent recognition that a subpopulation of CD4+ T cells called Treg that help control immune responses and prevent autoimmunity are selected in the thymus has led us to extend this work on the nature of the signals that determine the lineage choice of T cells in the thymus, focusing on whether CD4+ Treg follow the "signal duration" rule we established for the CD4/CD8 lineage choice, but with a greater duration requirement than the bulk of CD4 T cells. These studies will provide new insights into how a crucial T cell subpopulation involved in immune regulation is generated.